Bone loss and osteoporosis are major public health problems in the elderly. With people in the United States living longer than before, the number of people that will develop age-related bone loss and osteoporosis is expected to rise drastically in the coming decades. Osteoporosis not only presents problems in and of itself, but with joint replacement and musculoskeletal disorders requiring manipulation and repair of bone or boney tissue, depleted bone mass presents additional problems to an aging population.
Bone is comprised of several different cell types. Osteoblasts lay down new bone from the minerals present in the extracellular milieu around the cells. Osteoclasts remove old bone, releasing the minerals compiled within bone back into the extracellular matrix. This balance between adequate new bone being deposited and old bone being removed is what gives bone its extremely beneficial properties. Osteoblasts originate from mesenchymal stem cells while osteoclasts originate from hematopoietic stem cells.
Osteoblast differentiation is a crucial aspect of bone formation and remodeling. Osteoporosis is one disorder that reflects a flaw in this delicate balance. The process of new bone formation involves the recruitment of osteoprogenitor cells that, with the appropriate stimulation, undergo proliferation and differentiate into preosteoblasts and then into mature osteoblasts to synthesize inorganic matrix into mineralized bone.
Parathyroid hormone (PTH) is a major systemic regulator of the concentrations of calcium, phosphate, and active vitamin D metabolites in blood and of cellular activity in bone. PTH is the only anabolic agent clinically used to treat osteoporosis (Rosen, 2004, Trends Endocrinol. Metab. 15:229-233). Intermittent PTH treatment can lead to an increase in bone mass and strength with a corresponding decrease in fracture risk, whereas continuous PTH impairs bone quality and can result in bone pain and pathological fractures (for review, see Murray et al., 2006, Endocrine Reviews, 26(1):78-113). The cellular and molecular mechanisms that mediate the remarkably different effects of intermittent and continuous PTH are important but incompletely understood. In addition, PTH is a major regulator for kidney function and has been implicated in chronic kidney disease.
The amino-terminal region of PTH is known to be both necessary and sufficient for full activity at PTH/PTHrP receptors (PTH1Rs), which mediate the classical biological actions of the hormone. Additionally, it is well known that multiple carboxyl-terminal fragments of PTH (cPTH fragments) are present in blood, where they comprise the major form(s) of circulating hormone. These cPTH fragments have long been regarded as inert by-products of PTH metabolism since they neither bind to nor activate PTH1Rs. Certain observations extending over the past 20 years point to the existence of novel large carboxyl-terminal PTH fragments in blood and to receptors for these fragments that appear to mediate unique biological actions in bone and other tissues (Murray et al., 2006, Endocrine Reviews, 26(1):78-113; Divieti et al., 2005, Endocrinology, 146(4):1863-1870). While Divieti demonstrated that certain domains within cPTH are necessary for binding to a putative cPTH receptor, they have not identified or characterized any such receptor (Divieti et al., (2005) Endocrinology, 146(4):1863-1870).
The identification of novel receptors for PTH and PTH fragments provides a novel therapeutic target for the treatment of bone-related diseases and kidney disease.